A number of diagnostic and therapeutic medical procedures require the administration of certain organic compounds as contrast enhancing agents in order to enhance the quality of the procedure. These procedures include: contrast-enhancing agents for Magnetic Resonance Imaging (MRI), Computerized Tomography (CT) and X-ray.
The desire for early detection and treatment of metastatic disease has been the motivation for many recent advances in the fields of radiology and nuclear medicine. In particular, significant advances have been made to improve upon noninvasive techniques for visualizing internal organs using radiography and radioisotope scanning. The use of CT instead of conventional X-ray techniques allows for a more sophisticated visualization of the tissues and organs being studied. In addition, many CT agents have now been developed which provide a further advantage over conventional X-ray radiopaques in that they are more site specific.
Weichert et al. of the University of Michigan have studied the use of halogenated triglyceride compounds as liver and hepatocyte site-specific CT agents. In U.S. Pat. No. 4,873,075, this group at the University of Michigan disclosed polyiodinated triglyceride analogs as radiologic agents. The triglyceride compounds are composed of a triglyceride backbone structure that is 1,3-disubstituted or 1,2,3-trisubstituted with, in some embodiments, a 3-amino-substituted-2,4,6-triiodophenyl aliphatic chain wherein the chain has a structure similar to that of naturally occurring fatty acids.
MRI as opposed to CT has the advantage that it exhibits superior soft tissue differentiation. The two most widespread applications of MRI take advantage of the nuclear magnetic resonance of hydrogen (.sup.1 H) or fluorine (.sup.19 F). .sup.19 F MRI has the added advantage over .sup.1 H MRI in that while .sup.19 F has an NMR sensitivity nearly equivalent to that of .sup.1 H, it demonstrates negligible biological background.
While .sup.19 F MRI provides significant advantages over other imaging techniques, the success of the imaging agents being used depends on such qualities as ease of synthesis, site-specificity, resistance to hydrolysis in-vivo, a sufficient amount of signal and a high signal-to-noise ratio. In some instances, these desired qualities may actually be mutually exclusive. For example, the signal of a .sup.19 F MRI contrast agent can be increased by adding additional fluorines. However, depending on where the fluorine substituents are attached to the imaging agents being used, the fluorine containing molecules may exhibit different spectral resonance lines. This results in insufficient intensity of the signal of interest relative to noise which leads to a low signal-to-noise (S/N) ratio or band broadening and blurred images due to multiple resonances. As a result, high doses of the imaging agent or long imaging times are required.
The use of 3,5-bis(trifluoromethyl)aryl compounds, such as 1,3-bis[3',5'-di(trifluoromethyl)phenylacetyl] 2-oleoyl glycerol, for site-specific delivery of fluorine MRI agents has been disclosed by Weichert et al. (Abstracts of the Seventh Annual Meeting of the Society of Magnetic Resonance in Medicine (1988) 1; 484). This compound has the advantage that it exhibits only a single resonance frequency. However, it suffers from the problem of having only a limited number of fluorine equivalents per molecule.
The problem of insufficiency of signal was addressed by Rogers et al. with the development of perfluoro-tert-butyl (PFTB) reporter groups with each having 9 magnetically equivalent .sup.19 F nuclei. It was recognized that these compounds provide a mono-resonant fluorine reporter group making these types of compounds practical for MRI measurements. Rogers et al., Synthesis of Reporter Groups for Fluorine-19 NMR; a New Class of Imaging and Spectroscopic Compounds, Abstracts of the Eighth Annual Meeting of the Society of Magnetic Resonance in Medicine (1989) 2, 819; U.S. Pat. No. 5,116,599. However, known methods of introducing PFTB reporter groups are complicated and often involve steps that would destroy the biological activity or geometry of host compounds and thus interfere with their ability to efficiently target specific organs or tissues.
Therefore, there exists a need to provide for a class of .sup.19 F-MRI imaging agents which can overcome the aforementioned disadvantages.